AUTHOR AND EDITOR INFORMATION

Section 1 of 9  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• References

INTRODUCTION

Section 2 of 9  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• References

Background

Melanoma is a cutaneous malignancy of melanocytes, which are pigment-producing cells derived from the neural crest. Melanoma constitutes 3% of all cancers diagnosed in the United States. The incidence of melanoma is increasing faster than that of any other malignant neoplasm, except for lung cancer in women. For someone born in the United States in 2000, the projected lifetime risk of developing melanoma is 1 in 75. Melanoma is the most lethal form of skin cancer and the third most common malignancy causing CNS metastases, after lung and breast cancer. While early recognition and surgical excision of a cutaneous primary can be curative, treatment options for metastatic disease are limited and the prognosis becomes guarded.

Primary intracranial melanoma can arise from the leptomeninges or dura mater. Primary ocular melanoma is well recognized; however, orbital involvement usually is secondary to local invasion from an ocular, sinus, or CNS source or from hematogenous spread from a cutaneous or visceral site. Neurocutaneous melanosis is a congenital disorder in which infants with giant hairy melanocytic nevi have associated leptomeningeal melanocytosis involving the brain and/or spinal cord. This leptomeningeal invasion can cause severe neurological compromise or death.

Secondary CNS melanoma most often results from hematogenous spread from a known or unknown primary tumor. This chapter focuses on secondary CNS melanoma.

Pathophysiology

The 4 major histologic types of primary cutaneous melanoma are superficial spreading, nodular, acral lentiginous, and lentigo maligna melanoma. These tumors differ in their histologic and, possibly, biologic characteristics. Metastases reach the CNS via hematogenous spread of tumor cells. Tumor cells are released into the circulation, arrest in end arteries, penetrate the blood-brain barrier, enter the CNS, and establish growth in the new tissue. Neurotrophins can facilitate invasion by up-regulating enzymes such as heparanase, which destroy the extracellular matrix and basement membrane of the blood-brain barrier. Although initial metastatic foci involve the gray-white matter junction, any part of the brain can be involved, including the pituitary gland, cerebellum, and cerebral hemispheres. The tumors most often are multifocal and have a unique tendency to hemorrhage.

Other common sites of melanoma metastases are skin, subcutaneous tissue, spleen, liver, lymph nodes, lungs, gastrointestinal tract, and bone.

Frequency

United States

The prevalence of CNS metastases ranges from 10-40% in clinical series. Brain metastases are present in up to two thirds of patients with disseminated malignant melanoma.

Mortality/Morbidity

The brain is the initial site of metastasis in 12-20% of patients. The average time between first diagnosis of a cutaneous primary and discovery of CNS metastases is 45 months. Metastatic melanoma to the CNS is incurable. Treatment is aimed at tumor debulking, symptom relief, and palliation.

Race

Melanoma is 10 times more common in fair-skinned Caucasians than in dark-skinned individuals.

Sex

No sex predilection has been reported.

CLINICAL

Section 3 of 9  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• References

History

• Individuals at highest risk for melanoma include the following:
• • Individuals with fair skin, blue eyes, freckles, and red or blond hair
  • People who tan poorly, burn easily, and have a history of blistering sunburn in the past
  • People with a history of nonmelanoma skin cancer
  • People with numerous melanocytic nevi
  • People with atypical nevi
  • Individuals with a family history of melanoma or atypical nevi
• Elicit history of previous melanoma.
• • Date of diagnosis
  • Location of melanoma on body
  • Method of treatment (eg, type of excision, margin taken, whether reexcision was recommended and done)
  • Details from the pathology report (eg, gross appearance, excisional margin, histological type, depth of tumor, growth phase, presence of ulceration, involvement of blood vessels or lymphatics)
  • Stage of previous melanoma
• Ask patient about new or changing skin lesions.
• • Does the patient have concerns about any skin lesions?
  • Has the patient ever had any suspicious moles removed?
  • Have any moles undergone changes in their shape, size, color, texture, and sensitivity (itching or burning)?
  • Has the patient had any bleeding or ulceration from any skin lesions?
• Occasionally, patients may present with brain metastases and an unknown primary. This phenomenon may be secondary to spontaneous regression of a primary lesion or de novo melanoma within the lymph nodes, gastrointestinal tract, respiratory tract, or vagina. Approximately 10-20% of patients with an unknown primary have had a pigmented lesion removed in the past or have noted a pigmented cutaneous lesion that has involuted.
• Question all patients about symptoms suggestive of CNS metastases and other organ involvement.
• • Headache
  • Nausea and vomiting
  • Visual changes
  • Seizures
  • Confusion or personality change
  • Fatigue
  • Fever, night sweats
  • Cutaneous nodules near or distant to primary site
  • Cough, chest pain, new respiratory symptoms
  • Gastrointestinal bleeding
  • Bone pain

Physical

• Cutaneous examination
• • Document skin phototype and presence of actinic skin damage.
  • Carefully examine entire cutaneous surface, including the scalp, mucous membranes, and perianal and genital regions.
  • Identify any pigmented skin lesions that are asymmetric, have an irregular border, contain 2 or more colors, or are friable, bleeding, ulcerated, or polypoid.
  • Check primary surgical site for evidence of subcutaneous nodules indicating local recurrence or in-transit disease.
• Reticuloendothelial examination
• • Lymphadenopathy, particularly draining lymph nodes at the primary site
  • Hepatosplenomegaly
• Neurologic examination
• • Level of consciousness
  • Mental status examination
  • Cranial nerve abnormalities, including funduscopy for papilledema
  • Upper motor neuron signs or sensory deficits
  • Cerebellar ataxia
  • Speech abnormalities
  • Hyperreflexia
• Breast, rectal, renal, thyroid, and respiratory examination to search for other possible tumors in the differential diagnosis of CNS metastases

DIFFERENTIALS

Section 4 of 9  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• References

WORKUP

Section 5 of 9  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• References

Lab Studies

• Specific blood tests for intracerebral metastatic melanoma do not exist.
• Blood tests are based on differential diagnosis to help rule out certain diagnoses. Different presenting symptoms, such as acute confusion versus fever and meningismus, guide the differential diagnosis and subsequent serum investigations.
• Blood tests can help identify sequelae of brain metastases, such as hyponatremia in inappropriate antidiuretic hormone secretion or hypernatremia in diabetes insipidus. An isolated high level of lactic dehydrogenase can be presumptive evidence of metastatic disease. Serum lactate dehydrogenase levels are now part of the American Joint Committee on Cancer staging system for patients with metastatic melanoma.

Imaging Studies

• CNS metastases are characterized by solitary or multiple brain lesions of different sizes and locations. Significant perilesional edema is usually present.
• Contrast-enhanced MRI is the most sensitive imaging method to document CNS metastases, and it is preferred over contrast-enhanced CT. Contrast-enhanced CT scan can demonstrate features of metastatic disease; however, small metastases and leptomeningeal spread may be missed.
• MRI
• • MRI features of melanoma can be identical to those of certain other metastatic tumors because of the propensity of all these tumors to hemorrhage. The neoplasms most characterized by hemorrhage into CNS metastases can be remembered by the mnemonic MATCH: melanoma, anaplastic lung carcinoma, thyroid carcinoma, choriocarcinoma, hypernephroma.
  • Most CNS metastases classically appear as multiple areas of hypointensity on T1-weighted MRI and heterogeneous hyperintensity on T2-weighted MRI.
  • In addition, melanoma can be hyperintense on T1-weighted MRI and hypointense on T2-weighted MRI because of the melanin content of the tumor.
• The presence of hemorrhage may alter MRI signal intensity and further complicate the radiological diagnosis.
• Contrast administration reveals ring, homogeneous, or nodular enhancement of the tumors; leptomeningeal or dural enhancement occurs if the tumor has invaded these sites.
• Enhanced CT scan
• • With smaller tumors, solid enhancement is seen.
  • In large tumors, ringlike enhancement is seen.
• Nonenhanced CT scan
• • Most metastases are isodense with surrounding brain tissue and may be missed.
  • Perilesional edema may be the only finding.
• Patients with suspected brain metastases should undergo other imaging studies to determine whether other organ involvement exists, as this will influence management.
• • Chest radiographs may reveal hilar adenopathy, single or multiple metastatic nodules, or pleural effusions.
  • Chest and abdominal CT scans may further delineate pulmonary disease and identify intra-abdominal metastases.
  • Contrast bowel studies may reveal bowel metastases; this may be indicated in patients with anemia or blood in the stool.
  • Radionuclide bone scan is indicated for suspected bony metastases.
  • Whole-body positron emission tomography (PET) scan is a highly sensitive and specific modality in the detection of melanoma metastases and in identifying recurrent disease.
    • PET scanning detects malignant tumors based on increased glucose metabolism seen in malignant cells compared with normal surrounding tissue.
    • The radioisotope used, F-18 fluorodeoxy-D-glucose (FDG), is a glucose analog. FDG is taken up by normal and cancerous tissue and becomes phosphorylated and trapped within cells. Because cancer cells have markedly increased glucose metabolism compared with baseline tissue, the increased FDG uptake is easily identified.
    • PET scanning more accurately identifies melanoma metastases than CT scan, MRI, ultrasonography, or physical examination in most tissues, except the brain and lungs.
    • Unfortunately, PET scanning is of limited use in localizing CNS metastases because of the extensive baseline glucose metabolism of the brain.

Procedures

• Stereotactic brain biopsy by a neurosurgeon is usually not necessary if the patient has a known primary and if the imaging is compatible with melanoma.

Histologic Findings

Parenchymal metastases are well-circumscribed nodules of various sizes that may be solid or partially cystic. They are surrounded by marked edema and may be filled with hemorrhage or necrotic debris.

• Certain histopathologic findings in the cutaneous primary lesions are important markers for metastatic spread. Tumor thickness and the presence of tumor ulceration are the single most important prognostic factors.
  • Tumor thickness: Tumor thickness is measured from the stratum granulosum to the deepest dermal tumor cells. The thicker the tumor, the worse the prognosis.
  • Tumor ulceration: The presence of epidermal necrosis is an adverse prognostic sign.
  • Increased tumor vascularity, lymphovascular invasion, the presence of microsatellites are all negative prognostic factors.
  • High mitotic index and lack of tumor-infiltrating lymphocytes may also portend a poor prognosis.
  • If tumor tissue is available, identification of the brain lesion histologically can be challenging because the tumor may be poorly differentiated. In this case, special melanin stains, such as S100, Melan-A, or homatropine methylbromide (HMB) 45, can be helpful.

TREATMENT

Section 6 of 9  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• References

Medical Care

Melanoma that metastasizes to the CNS is incurable. Treatment is aimed at tumor debulking, symptom relief, and palliation. The patient usually can be monitored on an outpatient basis. Inpatient care may be required for patients who require evaluation, surgery, or palliative radiotherapy. The use of steroids provides symptom relief by decreasing cerebral edema.

Treatment options are based on the number and size of CNS lesions and the presence of extracranial disease. Several comprehensive reviews of the treatment of CNS melanoma metastases are available (Bafaloukos, 2004; Tarhini, 2004; Douglas, 2002; Wong, 2004). A brief summary of these literature reviews follows.

• Whole brain radiation therapy
  • Radiotherapy is effective for palliation. Improvement in neurological deficits post–whole brain radiation therapy (WBRT) is well documented.
  • WBRT can be used for solitary and multiple brain metastases.
  • No increase in overall survival is seen if used alone.
  • Increased overall survival may be seen if WBRT is used in combination with tumor resection.
• Stereotactic radiosurgery
  • Stereotactic radiosurgery (SRS) involves high doses of radiation delivered to the tumor in one fraction, in a single session, with relative sparing of surrounding tissues.
  • SRS is used for single or multiple CNS metastases; patients with single lesions have a better outcome.
  • One of the main advantages of SRS is the treatment of surgically inaccessible metastases.
  • SRS (with or without WBRT) can provide effective local control comparable to surgery plus WBRT.
  • Rare side effects of SRS include CNS radiation necrosis that requires surgery or systemic steroids. This complication may be seen in 5-10% of patients receiving SRS.
  • Local tumor control rates with SRS are quoted as 76-97% in the literature.
  • Median survival with SRS ranges from 4-7 months.

Surgical Care

• Surgery is recommended for solitary brain metastases. The patient should have controllable systemic disease to be considered for surgery. However, surgical resection is still a viable option for symptomatic patients with one or more systemic metastases.
• Addition of postoperative WBRT is considered by some to be more effective than surgery alone in local tumor control, as microscopic foci are likely to exist even after complete tumor resection.
• Surgery can significantly improve neurological signs and symptoms; however, a proportion of patients undergoing brain surgery for melanoma can have postoperative worsening of their neurological symptoms.
• Limitations of surgery include the inaccessibility of deep-seated or multifocal CNS lesions. Some patients may be too ill to tolerate brain surgery.
• The effect of surgery on median survival is controversial.

Consultations

A multidisciplinary team consisting of a neurologist, neurosurgeon, medical oncologist, dermatologist, and radiation oncologist should manage complex cases of metastatic melanoma.

MEDICATION

Section 7 of 9  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• References

The goals of pharmacotherapy are to induce remission, prevent complications, and reduce morbidity. Chemotherapy in patients with CNS metastases is recommended for patients who are not surgical candidates or have multiple metastases.

Fotemustine is a phosphoalanine-modified nitrosourea. It effectively crosses the blood-brain barrier. Main adverse effects are leukopenia and thrombocytopenia. Overall response rates of 12% have been found in phase 2 European Organization for Research and Treatment of Cancer (EORTC) Melanoma Cooperative Group trials. These were partial responses only. Unfortunately, the use of fotemustine is limited by its marked myelosuppressive properties.

Temozolomide is an oral alkylating agent. It effectively crosses the blood-brain barrier and is used to treat some primary brain tumors. Major adverse effects of temozolomide are nausea, vomiting, and myelotoxicity (thrombocytopenia and lymphopenia). Temozolomide has been studied as a single agent and in combination with other modalities. Temozolomide is at least as effective as dacarbazine (DTIC), the drug used historically for metastatic melanoma. It has the advantage of oral administration, and it demonstrates superior blood-brain barrier penetration.

In a recent phase II trial, overall response rates of 40% (partial responses and stabilizing disease only) were found. Temozolomide was used as single agent chemotherapy in 21 patients with CNS melanoma, in a more frequent dosing regimen than usual (75 mg/m²/d for 6 out of every 10 wk).

In an attempt to correct the profound lymphopenia seen in patients taking temozolomide, the drug was used in combination with GM-CSF, low-dose IL-2, and interferon alpha in a phase I/II study. This regimen had a favorable effect upon myelotoxicity, with cytopenias that were manageable on an outpatient basis.

Temozolomide has also been studied with a number of other modalities such as docetaxel, cisplatin, WBRT, and thalidomide, with variable results.

Summary of treatment options for metastatic melanoma to the brain is as follows:

• For 1-3 lesions: Consider surgery plus or minus WBRT, or SRS plus or minus WBRT.
• For large or multiple CNS metastases: Consider WBRT or chemotherapy.

Drug Category: Chemotherapy and hormonal therapy

These agents inhibit cell growth and proliferation.

FOLLOW-UP

Section 8 of 9  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• References

Further Inpatient Care

• Inpatient care may be required for patients who require evaluation, surgery, or palliative radiotherapy.
• Palliative care should include the following:
• • Attention to pain
  • Emotional and spiritual support
  • Nonsurgical treatment of symptoms of increased intracranial pressure (ie, steroids)

Further Outpatient Care

• The patient usually can be monitored on an outpatient basis.

Complications

• Secondary CNS melanoma is uniformly fatal. Death usually results because of increased intracranial pressure or destruction of vital brain tissue. The deterioration can be insidious or acute.
• Focal neurological signs are very common and may lead to significant morbidity.
• Patients may present with sudden catastrophic neurological events from hemorrhage into a tumor.

Prognosis

• Relentless progression of clinical signs and symptoms is seen in most patients once they present with evidence of CNS disease.
• Patients with solitary brain metastases, no lung or visceral metastases, and patients whose brain metastases were present upon diagnosis have a more favorable prognosis.
• Patients with concomitant visceral disease have a worse prognosis.
• Long-term survival has been described in patients who have had surgical resection of a single metastatic tumor.
• Median overall survival is 3.8 months.

REFERENCES

Section 9 of 9

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• References

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Article Last Updated: Sep 5, 2006